Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([CH3:12])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Nc1cccc(Br)n1
Product: Cc1cn2c(Br)cccc2n1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 6-bromopyridin-2-ylamine (1.0 g, 5.6 mmol) and 1-chloropropan-2-one (0.5 mL, 6.3 mmol) in IMS (4 mL) was stirred at reflux for 36 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (20 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. After the solvents were removed, the residue was purified by flash chromatography (Si—PPC, MeOH:Et2O, gradient 0:100 to 10:100) to give 5-Bromo-2-methylimidazo[1,2-a]pyridine as a yellow oil (547 mg, 45%). LCMS (Method H): RT=0.31 min and 2.04 min, [M+H]+ 211(79Br) and 213(81Br)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16](=[O:36])[N:17]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:19][CH:20]=3)=[CH:11][C:10]=2[F:37])[CH:5]=[CH:4][N:3]=1.[CH3:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41]C.ClC(OC1C=CC=CC=1)=[O:47].N1CCCC1>C1COCC1>[CH2:29]([N:17]1[C:16](=[O:36])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([N:40]4[CH2:43][CH2:44][CH2:38][CH2:39]4)=[O:47])[CH:7]=3)=[C:10]([F:37])[CH:11]=2)=[CH:20][N:19]=[C:18]1[NH:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(Oc2ccc(-c3cnc(Nc4ccc(F)cc4)n(Cc4ccccc4)c3=O)cc2F)ccn1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(Nc1cc(Oc2ccc(-c3cnc(Nc4ccc(F)cc4)n(Cc4ccccc4)c3=O)cc2F)ccn1)N1CCCC1
Reaction time: 0.67 h
Yield: 11.7 %

Procedure:
5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (238 mg, 0.478 mmol) was dissolved in THF (4.0 ml) and Et3N (0.17 ml, 1220 μmol) and phenyl chloroformate (0.13 ml, 1.0 mmol) were added. The reaction was stirred under nitrogen, and after 40 minutes, pyrrolidine (0.60 ml, 7.2 mmol) was added. Stirring was continued at room temperature, until LCMS analysis indicated the formation of the product. The reaction was quenched with saturated ammonium chloride (10 ml) and extracted with DCM (3×20 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (30:1->20:1 DCM/MeOH). The fractions with product were collected, concentrated, and washed with Et2O and then with acetone. The suspension was filtered, and the solid was collected and dried in vacuo to afford the desired title compound N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (33.2 mg, 0.0558 mmol, 4% over 3 steps). MS (ESI pos. ion) m/z: 595 (MH+). Calc'd exact mass for C33H25F2N6O3: 594. 1HNMR (400 MHz, CDCl3): 8.06 (d, J=6.4 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.68 (dd, J=10.4 Hz, 2.0 Hz, 1H), 7.51-7.39 (m, 6H), 7.22 (t, J=8.0 Hz, 1H), 7.15 (dd, J=9.2 Hz, 5.2 Hz, 2H), 7.06-6.99 (m, 3H), 6.57 (dd, J=5.2 Hz, 3.2 Hz, 1H), 6.44 (s, 1H), 5.49 (s, 2H), 3.49-3.43 (m, 4H), 1.99-1.94 (m, 4H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1)[CH2:7][CH2:8][CH3:9].[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:6][CH2:7][CH2:8][CH3:9])=[N:12][C:13]=12
Reactant: BrBr
Reactant: CCCCNc1ccn2nccc2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
Sodium acetate [127-09-3] (0.7 g, 8.9 mmol) was added to a solution of butyl-pyrazolo[1,5-a]pyrimidin-5-yl-amine (1.1 g, 5.9 mmol) in glacial acetic acid (100 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.3 mL, 6.4 mmol) was added drop by drop into the ambient temperature, buffered, acetic acid reaction solution over 5 minutes. Upon completion of the bromine addition, the suspension was allowed to stir for a further 15 minutes then was slowly poured into 500 mL of stirred water. Saturated aqueous sodium bicarbonate was added to the stirred suspension until pH of the supernatant was determined to be approximately 8 by pH paper, then the suspension was extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel eluted with 60% (v/v) ethyl acetate/heptane) to provide 1.2 g of off white solid, mp. 94-95° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1.31-1.44 (m, 2 H) 1.56 (quin, J=7.20 Hz, 2 H) 3.31-3.38 (m, 2 H) 6.28 (d, J=7.58 Hz, 1 H) 7.61 (t, J=5.05 Hz, 1 H) 7.85 (s, 1 H) 8.42 (d, J=7.58 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.67, 19.64, 30.53, 76.99, 100.87, 135.14, 143.03, 145.13, 156.09. LRMS (ESI) m/z 269.0/271.0 [(M+H)]+, calc'd for C10H13BrN4: 269.15.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:3](OCCCl)=[O:4].[C:16]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[CH2:17][OH:18].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:3]([O:18][CH2:17][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: CC(O)(C(=O)OCCCl)c1ccccc1
Reactant: CC(C)OC(=O)CO
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(C)(O)c1ccccc1

Procedure:
A 4.5 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxy-2-phenylpropionate, 0.25M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.30 g Lipase P30. After mixing for 8 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-phenylpropionate to the title compound was estimated (by GC, Method B) to be approximately 10%. The GC peak assigned to the title compound was confirmed by HRMS calcd for C13H14O5Tms (M-CH3) 323.1314, obsd 323.1366.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.[N:16]1[C:25]2[C:20](=[CH:21][C:22](C3(C#N)CC3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:11]3([CH:15]=[O:14])[CH2:13][CH2:12]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: N#CC1(c2ccc3ncccc3c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=CC1(c2ccc3ncccc3c2)CC1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Diisobutylaluminum hydride in THF (1.0 M, 96 mL, 0.096 mol) was added to a solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 0.0639 mol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to −5 to 0° C., and stirred at that temperature for 3 h. The mixture was re-cooled to −60° C. Isopropyl alcohol (10 mL) was carefully added dropwise. After stirring for 30 min, the mixture was warmed to −5 to 0° C. The mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered through a pad of silica gel and washed with ethyl acetate in hexanes (40%). The filtrate was concentrated to yield the desired 1-quinolin-6-ylcyclopropanecarbaldehyde (12 g, 95.1%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH2:8][CH:9]=[C:10]([CH:12]=O)[CH:11]=[C:5]2[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=CC1=CCC2NC(=O)COC2=C1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)OCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A mixture of 3-oxo-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde (0.5 g, 2.8 mmol), 1-(4-methyl-phenyl)-piperazine (0.5 g, 2.8 mmol), acetic acid (0.17 g, 2.8 mmol) and sodium triacetoxyborohydride (1.2 g, 5.9 mmol) in 20 mL of 1,2-dichloroethane is stirred at room temperature for 3 hours. The reaction is quenched with 50 mL of water, and the layers are separated. The aqueous phase is extracted with ethyl acetate (3×50 mL). The organic phases are combined and dried over sodium sulfate. Evaporation of the solvent gives a solid which is recrystallized twice from acetonitrile to give 0.31 g (33% yield) of 7-[4-(4-methyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazine-3-one; mp 208-210° C.
Reaction SMILES: C(P([C:10]([CH3:13])([CH3:12])C)C(C)(C)C)(C)(C)C.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](O[Na])([CH3:24])([CH3:23])C>C1(C)C=CC=CC=1>[C:15]1([N:14]([C:12]2[CH:10]=[CH:13][CH:23]=[CH:21][CH:24]=2)[C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:23]3[CH:21]=[CH:24][CH:13]=[CH:10][CH:12]=3)=[CH:16][CH:17]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)O[Na]
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 0.66 weight % toluene solution 150 μl of tri-t-butylphosphine was added to a toluene 50 ml solution of 4-bromo-triphenylamine 5.00 g, aniline 1.72 g, tris(benzylideneacetone)dipalladium (0) 282 mg and t-butoxysodium 2.07 g, and the mixture was stirred at room temperature for 5 hours. After finishing the reaction, the mixture was filtered through celite, and the filtrate was extracted with toluene. This was concentrated under reduced pressure, and the resulting crude product was subjected to column refining to obtain 4.20 g of pale yellow powder of N,N,N′-triphenyl-1,4-phenylenediamine.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:19]1[CH:20]=[CH:21][C:22]([O:29][CH3:30])=[C:23]([CH:28]=1)[C:24](OC)=[O:25])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.Cl.OC(C1C=CC(OC)=C(C=1)C(OC)=O)C[N:35]1CCN(C2C=CC=CC=2C)CC1.COC(=O)C1C=C(C(O)CN2CCN(C3C=CC=CC=3)CC2)C=CC=1OC>>[ClH:1].[OH:2][CH:3]([C:19]1[CH:20]=[CH:21][C:22]([O:29][CH3:30])=[C:23]([CH:28]=1)[C:24]([NH2:35])=[O:25])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3OC)CC2)ccc1OC
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC
Agent: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3)CC2)ccc1OC
Agent: Cl
Product: COc1ccc(C(O)CN2CCN(c3ccccc3OC)CC2)cc1C(N)=O

Procedure:
Following essentially the same procedure but substituting methyl 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride and methyl 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride for the methyl-5-[1-hydroxy-2-(4-phenyl-1-piperazinyl)ethyl]-2-methoxybenzoate above results in the preparation of 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzamide hydrochloride, having a m.pt. of 247°-8° C. (dec.) and 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzamide hydrochloride, having a m.pt. of 214°-6° C. (dec.), respectively.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH3:28])[CH3:14]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH:28]=[O:2])[CH3:14]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCOC(=O)CCCOc1cccc(C)c1C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1cccc(C)c1C=O
Temperature: 64 °C
Yield: 205.6 %

Procedure:
A mixture of copper(II) sulfate pentahydrate (21.98 g, 88.06 mmol) and potassium persulfate (71.42 g, 264 mmol) in water (396 mL) was heated to 63-65° C. to obtain a blue colored solution. Then, a solution of 4-(2,3-dimethyl-phenoxy)-butyric acid ethyl ester (20.81 g, 88.06 mmol) in acetonitrile (220 mL) was added at the above temperature. The resulting light green solution was refluxed for 40 minutes. Then, the reaction mixture was cooled to ˜5° C. in order to precipitate most of the inorganic solids. The resulting solids were collected by filtration and the solid cake was washed with dichloromethane (1.0 L). The two layers of filtrate were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatography eluting with 5-10% ethyl acetate in hexanes to obtain 4-(2-formyl-3-methyl-phenoxy)-butyric acid ethyl ester (45.32 g, 94%) as a colorless oil: EI(+)-HRMS m/e calculated for C14H18O4 (M+)+ 250.1205, found 250.1202.
Reaction SMILES: [C:1]1([CH:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([N:12]1[CH2:11][CH2:10][C:9]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8]2)[CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: c1ccc(C2OC3(CCNCC3)c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of 6.0 g. of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 2.4 g. of triethylamine, and 50 ml. of chloroform is added dropwise a solution of 2.0 g. of acetyl chloride and 50 ml. of chloroform. The mixture is stirred for 2 hours at room temperature, washed with water, dried over sodium sulfate, and concentrated. The residue is recrystallized from chloroform to provide colorless crystals, m.p. 128°-130°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:13].[NH3:14]>O1CCCC1>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:4](=[N:3][O:2][CH3:1])[C:5]([NH2:14])=[O:13]
Reactant: CON=C1C(=O)Oc2ccccc21
Reactant: N
Solvent: C1CCOC1
Product: CON=C(C(N)=O)c1ccccc1O
Yield: 36.4 %

Procedure:
5 g (0.028 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) (WO-A 9524396) in 100 ml of tetrahydrofuran are stirred with 20 ml of 25% strength aqueous ammonia solution at 20° C. for 2 hours. The solvent is then distilled off under reduced pressure, the residue is poured onto water and extracted with ethyl acetate, the organic is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol, affording 2 g (36.4% of theory) of 2-(2-hydroxy-phenyl)-2-methoxyimino-acetamide.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:46][C:47](=[O:59])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:17][S:18][CH2:19][C@H:20]([NH:28][C:29]([O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[C:47]([O:46][C@H:16]([CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:17][S:18][CH2:19][C@@H:20]([C:21]([OH:23])=[O:22])[NH:28][C:29](=[O:30])[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)(=[O:59])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC

Procedure:
A solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl thio)propane-1,2-diyl didodecanoate (11) in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hr). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vacuo. The resulting waxy solid was used without further purification.
Reaction SMILES: C(C1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH2:18][F:19])([CH2:16][F:17])[CH:4]=1)#N.[C:20]([OH:23])(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[F:17][CH2:16][C:5]1([CH2:18][F:19])[CH:4]=[C:21]([C:20]([OH:23])=[O:22])[C:12]2[CH:11]=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:7]=2[O:6]1
Reactant: CC(=O)O
Reactant: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 0.93 g of 4-cyano-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran, 20 ml of acetic acid, 10 ml of water and 10 ml of concentrated sulfuric acid was refluxed with heating for 4.5 hours. When the reaction mixture was poured into ice water, crystals were separated out. Said crystals were dissolved with a sodium hydrogen carbonate solution and washed with methylene chloride. A water layer was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled to obtain 0.83 g of 2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxylic acid with a melting point of 171°-172° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].C([O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][C:19]=1[O:26][CH3:27])(=O)C.FC(F)(F)C(O)=[O:31]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:22](=[O:31])[C:21]1[CH:24]=[CH:25][C:18]([OH:17])=[C:19]([O:26][CH3:27])[CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C#N)ccc1OC(C)=O
Reactant: CCCCc1cc2ccccc2o1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)c(OC)c1
Reaction time: 2 h

Procedure:
A mixture of 17.4 g. (0.1 mol.) of 2-n-butyl-benzofuran and 19.1 g. (0.1 mol.) of 4-acetoxy-3-methoxy-benzonitrile in 20 ml. of trifluoroacetic acid is refluxed for three hours. The reaction mixture is cooled, diluted with 200 ml. of water and the resulting aqueous solution is extracted with ether. The extracts are concentrated to dryness and the residue is dissolved in 100 ml. of ethanol and heated with 20 ml. of 10% aqueous sodium carbonate for two hours. The mixture is concentrated, the residue extracted with ether and the extracts are dried and concentrated in vacuo to give 2-n-butyl-3-(3'-methoxy-4'-hydroxybenzoyl)-benzofuran.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>O1CCOCC1>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(F)c3)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluorobenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 60° C. for 30 minutes. The reaction liquid is worked up in the same manner as described in Example 1 whereby 2.05 g (yield: 71.5%) of powdery 3-(3-fluorobenzoyl)-2'-deoxy-3', 5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: Cl.Cl.C(O[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15]CCCCCCCCCCCCCCC)[CH:8]=1)C.[NH3:48]>C(O)C>[CH2:31]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:47])=[NH:48])[CH2:15][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)N)c1
Reaction time: 3 h
Yield: 74 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-benzimidate dihydrochloride (35.0 g., 0.05 mole) was dissolved in ethanol (150 ml.) and the mixture saturated with ammonia gas at 20° C. The mixture was held for 3 hours at 20° C., resaturated with ammonia gas at 20° C., and then stoppered and held overnight at room temperature. The mixture was evaporated in vacuo to a solid which was triturated with acetone (200 ml.), filtered, washed with water (4 × 100 ml.), triturated again with acetone (2 × 100 ml.), filtered and dried in vacuo overnight [22.0 g., 74% yield, Rf .42 (4:1, benzene:ethanol on silicic acid)]. The crude product was recrystallized from hot acetone (20.9 g., 70% yield, m.p.--forms a gel at 84° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11](C3C=CC=CC=3)[CH:12]=2)[N:7]=1.[Li]CCCC.C([O:39][B:40](OC(C)C)[O:41]C(C)C)(C)C.CO.ClCCl>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16](=[O:17])[NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:40]([OH:41])[OH:39])[CH:12]=2)[N:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(-c3ccccc3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
6-bromo-2-(furan-2-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.4 g, prepared as described above for compound 1) was dissolved in THF (15 ml) in a round-bottomed flask under argon atmosphere. The solution was cooled to −78° C., then n-BuLi (15% in hexanes, 1.0 ml, 1.5 eq) was added dropwise. The reaction was maintained at this temperature for 45 minutes, at which time triisopropylborate (0.376 g, 2.0 eq.) was added dropwise. The reaction was allowed to warm to RT and stirred for an additional 3 hours. The completion of the reaction was monitored on TLC using methanol:dichloromethane (1:9) as a mobile phase. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (10 ml), then was extracted with ethyl acetate (2*10 ml) which was discarded. The aqueous layer was added Conc.HCl to adjust pH up to 6-7. The solid was precipitated which further was filtered on Buckner funnel and washed with water (10 ml). The solid was dried to obtain (2-(furan-2-yl)-4-(pyridin-3-ylcarbamoyl)quinolin-6-yl)boronic acid (0.300 g) which was used as such in next step.